Carcinoma of the colon and rectum is currently the second leading cause of cancer-related mortality in the United States. Genetic susceptibility to this malignancy has been identified among individuals and families with familial adenomatous polyposis (FAP) and with hereditary non-polyposis colorectal cancer (HNPCC). However, the majority of colorectal cancer cases appear sporadic. There have been significant advances in understanding the genetic alterations associated with tumor progression pathways among individuals where the FAP gene (adenomatous polyposis coli; APC) is the first or an early event (the Aneuploid Pathway) as well as among HNPCC-affected individuals (the Mismatch Repair or MMR-Pathway). Central to the theme of this project is the hypothesis that the genetic alterations implicated in the Aneuploid- and MMR-Pathways of tumor progression are relevant to the diagnostic and therapeutic approaches of patients with sporadic colorectal cancers. This Program consists of three Projects of three Projects and three Core facilities. Project 1 has nine phase I/II clinical trials which will test multi- agent chemotherapy regimens including oral agents with our without pelvic radiation for patients with rectal cancer or metastatic colorectal cancer, respectively. Another goal of Project is to identify patients whose therapy an be rationally influenced by determination of genetic alterations associated with the Aneuploid-Pathway (Project 2) or MMR-pathway (Project 3) or tumor progression. It is expected that at least 230 tumors form clinical trip enrollees will be tested for MMR Status as well as the degree of expression of genes related to the Aneuploid Pathway. Investigators in Project 2 will use the APC system to further identify and characterize genes that influence the development of colorectal polyps/tumors. Additional studies of the Mom1 locus and a newly discovered tumor modifier named Mom2 will provide further insight into the Aneuploid-Pathway of colorectal tumor progression with the goal of prevention and therapeutic intervention. Project 3 researchers will continue to elucidate the structural and functional processes associated with mismatch repair genes now implicated in the development and progression of many hereditary and sporadic colorectal cancers. This work will enhance our understanding of the complex events in the MMR-pathway and also provide new diagnostic and prognostic methodologies to test in colorectal tumors.